U.S. patent application number 17/554842 was filed with the patent office on 2022-06-09 for anti-inflammatory and mydriatic intracameral solutions for inhibition of postoperative ocular inflammatory conditions.
The applicant listed for this patent is Omeros Corporation. Invention is credited to Gregory A. Demopulos, Vincent A. Florio.
Application Number | 20220175727 17/554842 |
Document ID | / |
Family ID | 1000006155662 |
Filed Date | 2022-06-09 |
United States Patent
Application |
20220175727 |
Kind Code |
A1 |
Demopulos; Gregory A. ; et
al. |
June 9, 2022 |
Anti-Inflammatory and Mydriatic Intracameral Solutions for
Inhibition of Postoperative Ocular Inflammatory Conditions
Abstract
The present invention provides methods for inhibiting
postoperative inflammatory conditions following ophthalmologic
surgical procedures by administering intraocularly during an
ophthalmologic surgical procedure a solution including a
nonsteroidal anti-inflammatory agent and an alpha-1 adrenergic
mydriatic agent, such as a liquid irrigation solution of ketorolac
and phenylephrine.
Inventors: |
Demopulos; Gregory A.;
(Mercer Island, WA) ; Florio; Vincent A.;
(Seattle, WA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Omeros Corporation |
Seattle |
WA |
US |
|
|
Family ID: |
1000006155662 |
Appl. No.: |
17/554842 |
Filed: |
December 17, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16276337 |
Feb 14, 2019 |
11234965 |
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17554842 |
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15836772 |
Dec 8, 2017 |
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16276337 |
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14953806 |
Nov 30, 2015 |
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15836772 |
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62086133 |
Dec 1, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/137 20130101;
A61K 31/405 20130101; A61K 31/192 20130101; A61K 31/4174 20130101;
A61K 31/407 20130101; A61K 9/0048 20130101 |
International
Class: |
A61K 31/407 20060101
A61K031/407; A61K 31/137 20060101 A61K031/137; A61K 31/405 20060101
A61K031/405; A61K 31/192 20060101 A61K031/192; A61K 31/4174
20060101 A61K031/4174; A61K 9/00 20060101 A61K009/00 |
Claims
1. A method for reducing the incidence or severity of a
postoperative inflammatory condition following an ophthalmologic
surgical procedure in a subject identified as having an elevated
risk of suffering from a postoperative inflammatory condition, the
method comprising: administering to the subject's intraocular
tissues during an ophthalmologic surgical procedure an effective
amount of a solution including a nonsteroidal anti-inflammatory
drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic
agent in an intraocular irrigation carrier.
2. The method of claim 1, wherein the NSAID is ketorolac and the
mydriatic agent is phenylephrine.
3. The method of claim 1, wherein the solution is administered by
irrigation of the intraocular tissues during the procedure or by
intraocular injection.
4. The method of claim 1, wherein the solution is administered by
irrigation of intraocular tissues during the procedure followed by
intraocular injection of a bolus of the solution at the end of the
procedure.
5. The method of claim 1, wherein the solution comprises
phenylephrine at a concentration of from 240 to 720 .mu.M and the
ketorolac is present at a concentration of from 44 to 134
.mu.M.
6. The method of claim 1, wherein a sufficient amount of the NSAID
and the mydriatic agent are included in the solution to maintain an
intraoperative pupil diameter of at least 6.0 mm during the
procedure.
7. The method of claim 1, wherein the solution is administered by
intraocular injection during a procedure in which another
therapeutic agent is injected intraocularly.
8. The method of claim 1, wherein the postoperative inflammatory
conditions is selected from the group consisting of toxic
anterior-segment syndrome, cystoid macular edema, acute
endophthalmitis, posterior capsule opacification, anterior capsule
contraction, herpes simplex virus keratitis after cataract surgery,
postsurgical hypotony, nylon suture toxicity, long-term corneal
endothelial cell loss after cataract surgery, corneal edema, iris
chafing, corneo-retinal inflammatory syndrome, scleritis,
episcleritis, vitreous wick syndrome, post-operational acute
iridocyclitis, uveitis, epiretinal deposits after cataract
extraction, reiterative membranous proliferation with giant-cell
deposits, toxic vitreitis, posterior synechia, postoperative
intraocular fibrin formation, incisional fibrosis, complications of
macular hole surgery, choroidal effusion, and hypopyon.
9. The method of claim 1, wherein the postoperative inflammatory
condition is cystoid macular edema or uveitis.
10. The method of claim 1, wherein the subject is at elevated risk
of a postoperative inflammatory condition because of a preoperative
physiologic condition or characteristic, a preoperative treatment
history, surgical trauma, or the surgical placement of a device
that is associated with an enhanced incidence of postoperative
inflammation.
11. The method of claim 1, wherein the subject is at elevated risk
of a postoperative inflammatory condition because of a preoperative
physiologic condition or characteristic including a preoperative
dilated pupil diameter of less than 6 mm, floppy iris syndrome,
uveitis, retinal vein occlusion, epiretinal membrane, being over 65
years of age, diabetes mellitus, diabetic macular edema, diabetic
retinopathy, macular degeneration, or systemic hypertension; a
preoperative treatment history including previous ocular surgery or
pharmacologic treatment with an alpha-1 adrenergic receptor
antagonist or latanoprost; surgical trauma including posterior
capsule rupture, secondary capsulotomy, iris incarceration,
retained lens material, or vitreous loss; and the surgical
placement of nylon sutures, iris-fixated intraocular lens or an
anterior chamber intraocular lens.
12. The method of claim 1, wherein the subject is at elevated risk
of a postoperative inflammatory condition because of being over 65
years of age or having diabetes mellitus.
13. The method of claim 1, wherein the effective amount is the
amount of the solution resulting in at least 90% inhibition of
baseline cyclooxygenase-1 and cyclooxygenase-2 activity levels in
ocular tissues for a period of at least six hours
postoperatively.
14. The method of claim 1, wherein the effective amount is the
amount of the solution resulting in at least 90% inhibition of
baseline cyclooxygenase-1 and cyclooxygenase-2 activity levels in
ocular tissues for a period of at least eight hours
postoperatively.
15. The method of claim 1, wherein the effective amount is the
amount of the solution resulting in at least 85% inhibition of
baseline cyclooxygenase-1 and cyclooxygenase-2 activity levels in
ocular tissues for a period of at least ten hours postoperatively.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of pending U.S.
patent application Ser. No. 16/276,337, filed Feb. 14, 2019, which
is a continuation of application Ser. No. 15/836,772, filed Dec. 8,
2017, now abandoned, which is continuation of prior U.S. patent
application Ser. No. 14/953,806, filed Nov. 30, 2015, now
abandoned, which claims the benefit of U.S. Provisional Application
No. 62/086,133 filed Dec. 1, 2014, the disclosures of each of which
are incorporated herein by reference in their entirety.
I. FIELD OF THE INVENTION
[0002] The present invention relates to methods of using liquid
pharmaceutical compositions including a nonsteroidal
anti-inflammatory agent and an alpha-adrenergic mydriatic agent for
intraocular administration during an ophthalmologic surgical
procedure to inhibit postoperative inflammatory conditions.
II. BACKGROUND OF THE INVENTION
[0003] Ophthalmologic surgery necessarily results in trauma to
delicate intraocular structures that induces prostaglandin
synthesis and the inflammatory cascade. The resulting inflammation
can result in the occurrence of excess inflammation and associated
postoperative inflammatory conditions, particularly in subjects
having a preoperative condition placing them at elevated risk for
postoperative inflammatory conditions or that may experience an
elevated level of surgical trauma.
[0004] Ocular surgery often requires the use of a physiologic
irrigation solution to facilitate the procedure and to protect and
maintain the physiological integrity of intraocular tissues.
Examples of ophthalmologic surgical procedures typically requiring
irrigation solutions include cataract extraction and lens
replacement and refractive lens exchange procedures, corneal
transplant procedures and vitreoretinal operations and
trabeculectomy procedures for glaucoma. Throughout the intraocular
surgery, a patient's pupil must be sufficiently dilated to permit a
clear operative field and to limit the trauma that can be
associated with the procedure. Pupil dilation (mydriasis) is
typically achieved by dilating the eye preoperatively by topical
administration of a mydriatic agent.
[0005] During the surgery, as the tips of surgical tools are
inserted into the anterior chamber of the eye and surgical trauma
is induced, the iris sphincter muscle tends to constrict (miosis),
reducing the window defined by the pupil. If pupil diameter is not
maintained adequately throughout the procedure, the risk of
injuring structures within the eye increases and the required
operating time is often prolonged. Clinically significant
reductions in pupil diameter are associated with an increase in
procedure-related complications, including posterior capsule tears,
retained lens fragments and vitreous leaks.
[0006] Many ophthalmologic surgeons may incorporate epinephrine
into the intraocular irrigation solution to assist in the
maintenance of pupil dilation. While epinephrine is a alpha- and
beta-adrenergic agonist, phenylephrine is an alpha-1 agonist that
is sometimes administered topically prior to surgery to promote
mydriasis, but phenylephrine is not approved in the United States
in a preservative- and bisulfite-free form for intraocular
administration.
[0007] It is also desirable to reduce postoperative pain and
irritation for patient comfort. Because of this, patients may be
treated preoperatively and/or postoperatively with a nonsteroidal
anti-inflammatory drug (NSAID). Ketorolac is an NSAID that is
commercially available in preserved form for ocular use.
Acular.RTM. from Allergan is a ketorolac tromethamine solution that
includes benzalkonium chloride 0.01% as a preservative, available
in 3-mL and 6-mL dropper bottles. Bedford Laboratories also
supplies ketorolac tromethamine in a concentrated form (15 mg or 30
mg in 1 mL or 60 mg or 300 mg in 10 mL) for injection for
intravascular or intramuscular administration. Allergan supplies a
preservative-free 0.45% ketorolac tromethamine ophthalmic solution,
which is formulated with carboxymethylcellulose sodium, sodium
chloride, sodium citrate dehydrate, in individual-use vials under
the tradename Acuvail.RTM.. Some ophthalmic surgeons also use
topical NSAIDs preoperatively in an attempt to preempt
intraoperative miosis. This approach to miosis prevention is not
optimal because intraoperative irrigation solution washes out
preoperatively delivered agents from the areas within the eye that
are bathed by the irrigation solution.
[0008] Approved by FDA in 2014, OMIDRIA.TM. (phenylephrine and
ketorolac injection) 1%/0.3%), Omeros Corporation, is an alpha
1-adrenergic receptor agonist and nonselective cyclooxygenase
inhibitor indicated for maintaining pupil size by preventing
intraoperative miosis and for reducing postoperative pain.
OMIDRIA.TM. is added to standard irrigation solution used during
cataract surgery or intraocular lens replacement. OMIDRIA.TM. is
not currently indicated for the reduction of postoperative
inflammation.
III. SUMMARY OF THE INVENTION
[0009] The present invention provides a method for inhibiting a
postoperative inflammatory condition following an ophthalmologic
surgical procedure. The method includes identifying a subject with
an elevated risk of suffering from a postoperative inflammatory
condition, which identification may be made preoperatively based on
a preexisting physiologic condition or characteristic, prior
treatment history, or pharmacologic history, and administering
intraocularly to the subject during an ophthalmologic surgical
procedure a solution including a nonsteroidal anti-inflammatory
drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic
agent in an intraocular irrigation carrier. The NSAID and the
mydriatic agent are included in the solution in amounts sufficient
to maintain intraoperative pupil diameter by promoting mydriasis
and inhibiting miosis, such as maintaining an intraoperative pupil
diameter of at least 6.0 mm during the procedure, and a sufficient
amount of the solution is administered for uptake of an amount of
the NSAID in ocular tissues sufficient for inhibition of
cyclooxygenases for a period of at least six hours postoperatively,
thereby inhibiting the postoperative inflammatory condition. In
other embodiments of the invention, the identification of an
elevated risk of postoperative inflammation may occur during the
procedure based on the nature of trauma incurred during the
procedure. In still other embodiments, the identification of an
elevated risk of a postoperative inflammatory condition may be made
intraoperatively and/or preoperatively.
[0010] Suitable NSAIDs for use in the solution administered in
accordance with the present invention include flurbiprofen,
suprofen, diclofenac, ketoprofen, ketorolac, indomethacin,
nepafenac and bromfenac, and suitable alpha-1 adrenergic receptor
agonists include phenylephrine, epinephrine, oxymetazoline and
naphazoline. In a preferred embodiment of the invention, the NSAID
is ketorolac and the mydriatic agent is phenylephrine. In another
embodiment the solution includes phenylephrine at a concentration
of from 240 to 720 .mu.M and ketorolac at a concentration of from
44 to 134 .mu.M. The phenylephrine and ketorolac may be suitably
included at a molar ratio of from 3:1 to 10:1 phenylephrine to
ketorolac.
[0011] In one embodiment of the present invention, administration
of the solution results in at least 85%, and preferably at least
90%, inhibition of baseline cyclooxygenase-1 (COX-1) and
cyclooxygenase-2 (COX-2) activity in ocular tissues for a period of
at least six hours postoperatively. In another embodiment of the
present invention, administration of the solution results in at
least 85%, and preferably at least 90%, inhibition of baseline
COX-1 and COX-2 activity in ocular tissues for a period of at least
seven hours postoperatively. In another embodiment of the present
invention, administration of the solution results in at least 85%
inhibition of baseline COX-1 and COX-2 activity in ocular tissues
for a period of at least eight hours postoperatively. In another
embodiment of the present invention, administration of the solution
results in at least 90% inhibition of baseline COX-1 and COX-2
activity in ocular tissues for a period of at least eight hours
postoperatively. In still another embodiment, administration of the
solution results in at least 85% inhibition of baseline COX-1 and
COX-2 activity in ocular tissues for a period of at least ten hours
postoperatively.
[0012] The method of the present invention may be used in any
ophthalmologic surgical procedure associated with a risk of
postoperative inflammation, including procedures requiring pupil
dilation and associated with postoperative inflammation, such as
cataract extraction and lens replacement, refractive lens exchange,
vitrectomy, retinal photocoagulation, retinal detachment repair,
macular hole repair, retroiris tumor or mass removal, posterior
sclerotomy and optic neurotomy, or in connection with the
inhibition of inflammatory conditions resulting from intravitreal
injections. In some embodiments, the solution of the present
invention is administered to irrigate intraocular tissues during
the procedure, such as continuously throughout the procedure. In
other embodiments, solution of the present invention is
administered by intraocular injection as part of the procedure. In
still other embodiments, the solution of the present invention is
administered by irrigation of intraocular tissues during the
procedure followed by intraocular injection of a bolus of the
solution at the end of the procedure. In still another embodiment,
the solution of the present invention is administered by
postoperative injection of a bolus of the solution at the end of
the procedure, for example following the identification of the
patient being at risk of a postoperative inflammatory condition due
to trauma incurred intraoperatively. In still another embodiment,
the solution is administered by intraocular injection
preoperatively, intraoperatively and/or postoperatively.
[0013] In another aspect of the invention, the method is used in a
procedure selected from vitrectomy, retinal photocoagulation,
retinal detachment repair, macular hole repair, retroiris tumor or
mass removal, posterior sclerotomy and optic neurotomy, or in
connection with the inhibition of inflammatory conditions resulting
from intravitreal injections.
[0014] Postoperative inflammatory conditions inhibited by the
methods of the present invention include, for example, toxic
anterior-segment syndrome, cystoid macular edema including
nonpseudophakic cystoid macular edema and pseudophakic
(Irvine-Gass) cystoid macular edema, acute endophthalmitis,
posterior capsule opacification, anterior capsule contraction,
herpes simplex virus keratitis after cataract surgery, postsurgical
hypotony, nylon suture toxicity, long-term corneal endothelial cell
loss after cataract surgery, corneal edema, iris chafing,
corneo-retinal inflammatory syndrome, scleritis, episcleritis,
vitreous wick syndrome, post-operational acute iridocyclitis,
uveitis, epiretinal deposits after cataract extraction, reiterative
membranous proliferation with giant-cell deposits, toxic vitreitis,
posterior synechia, postoperative intraocular fibrin formation,
incisional fibrosis, complications of macular hole surgery,
choroidal effusion, and hypopyon.
[0015] In other embodiments, the subject is identified as having an
elevated risk of a postoperative inflammatory condition because of
a preoperative physiologic condition or characteristic including
small pupil diameter (e.g., a dilated preoperative pupil diameter
of less than 6 mm), floppy iris syndrome, uveitis, retinal vein
occlusion, epiretinal membrane, advanced age (e.g., over 65,
elderly or geriatric), diabetes mellitus, diabetic macular edema,
diabetic retinopathy, macular degeneration, or systemic
hypertension; a preoperative treatment history including previous
ocular surgery or pharmacologic treatment with an
alpha-1-adrenergic receptor antagonist or latanoprost; surgical
trauma including posterior capsule rupture, secondary capsulotomy,
iris incarceration, retained lens material, or vitreous loss; and
the surgical placement of nylon sutures, iris-fixated intraocular
lens or an anterior chamber intraocular lens.
[0016] In a further aspect of the invention, the subject is
identified as having an elevated risk of a postoperative
inflammatory condition because of a preoperative physiologic
condition or characteristic selected from small pupil diameter
(e.g., a dilated preoperative pupil diameter of less than 6 mm),
floppy iris syndrome, uveitis, retinal vein occlusion, epiretinal
membrane, diabetic macular edema, diabetic retinopathy, macular
degeneration, or systemic hypertension; a preoperative treatment
history including previous ocular surgery or pharmacologic
treatment with an alpha-1-adrenergic receptor antagonist or
latanoprost; surgical trauma including posterior capsule rupture,
secondary capsulotomy, iris incarceration, retained lens material,
or vitreous loss; and the surgical placement of nylon sutures,
iris-fixated intraocular lens or an anterior chamber intraocular
lens.
[0017] The present invention also provides a method for inhibiting
a postoperative inflammatory condition following an ophthalmologic
surgical procedure by identifying a subject with a physiologic risk
of suffering from a postoperative inflammatory condition and
administering intraocularly to the subject during an ophthalmologic
surgical procedure a solution including a nonsteroidal
anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor
agonist mydriatic agent in an intraocular irrigation carrier,
wherein the NSAID and the mydriatic agent are included in the
solution in amounts sufficient for the maintenance of
intraoperative pupil diameter due to the intraoperative promotion
of mydriasis by the mydriatic agent and the intraoperative
inhibition of miosis by the NSAID, thereby reducing intraoperative
trauma, and for the inhibition of the postoperative inflammatory
condition by the intraoperative and postoperative anti-inflammatory
effect of the NSAID.
[0018] The present invention provides a method for inhibiting a
postoperative inflammatory condition following an ophthalmologic
surgical procedure by intraocular administration during an
ophthalmologic surgical procedure, to a subject at risk of a
postoperative inflammatory condition, a solution including a
nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1
adrenergic receptor agonist mydriatic agent in an intraocular
irrigation carrier. The NSAID and the mydriatic agent are included
in the solution in amounts sufficient to maintain intraoperative
pupil diameter by promoting mydriasis and inhibiting miosis, and a
sufficient amount of the solution is administered for uptake of an
amount of the NSAID in ocular tissues sufficient for inhibition of
cyclooxygenases for a period of at least six hours postoperatively,
thereby inhibiting the postoperative inflammatory condition.
IV. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The present invention will now be described in greater
detail, by way of example, with reference to the accompanying
drawings in which:
[0020] FIGS. 1-3 provide results from the clinical studies of
Example 1. FIG. 1 illustrates the mean (.+-.SEM) change from
baseline in mean pupil diameter (PD) over time to the end of
surgery. Pupil diameters were measured at 1-minute intervals from
baseline to the end of the procedure and at the end of cortical
cleanup from a video recording of the subject's surgery. FIG. 2
illustrates the maximum intraoperative pupil constriction at any
time during surgery resulting from the studies. FIG. 3 illustrates
the mean ocular pain visual analog scale (VAS) scores during the
early postoperative period (full analysis set population).
[0021] FIGS. 4-7 provide results from the intracameral dog study of
Example 2, and illustrate the mean concentrations of ketorolac in
ocular tissues of female dogs at specified time points after the
intracameral dosing of phenylephrine 1.0%/ketorolac 0.3% injection
in balanced salt solution. FIG. 4 shows ketorolac concentrations in
the cornea, lens capsule, iris-ciliary body (ICB), aqueous humor,
and anterior sclera. FIG. 5 shows ketorolac concentrations in the
bulbar and palpebral conjunctiva. FIG. 6 shows ketorolac
concentrations in the vitreous humor, retina, choroid-RPE
(peripheral), choroid-RPE (tapetum), and posterior sclera. FIG. 7
shows the mean percent inhibition of COX-1 and COX-2 in retinal
tissues at t=0 through t=10 hours.
V. DETAILED DESCRIPTION
[0022] The present invention provides a method for inhibiting a
postoperative inflammatory condition following an ophthalmologic
surgical procedure by intraocular administration during an
ophthalmologic surgical procedure, to a subject at risk of a
postoperative inflammatory condition, a solution including a
nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1
adrenergic receptor agonist mydriatic agent in an intraocular
irrigation carrier. The NSAID and the mydriatic agent are included
in the solution in amounts sufficient to maintain intraoperative
pupil diameter by promoting mydriasis and inhibiting miosis,
thereby reducing the potential for inflammation-inducing trauma to
intraocular structures. A sufficient amount of the solution is
administered for uptake of an amount of the NSAID in ocular tissues
sufficient for inhibition of cyclooxygenases for a period of at
least six hours postoperatively, thereby inhibiting or reducing the
likelihood or severity of the postoperative inflammatory
condition.
Ophthalmologic Surgical Procedures
[0023] The present invention may be utilized in a variety of
ophthalmologic surgical procedures that are associated with the
occurrence of postoperative inflammatory conditions, including
anterior segment procedures performed in the anterior chamber or
posterior chamber of the eye, and procedures performed in the
posterior segment of the eye, such as retinal procedures. In many
cases the procedure is an intracameral procedure. Suitably the
ophthalmologic surgical procedure during which the method of the
present invention is used is a procedure requiring dilation or
mydriasis of the pupil, to provide the surgeon an expanded
operative field and visualization of intraocular structures through
the dilated pupil. In accordance with the present invention, the
solution is administered intraocularly by irrigation and/or
injection during the procedure to maintain pupil diameter by
promoting mydriasis and inhibiting miosis, thereby reducing
surgical trauma to the iris and intraocular structures manipulated
through the iris. The solution of the present invention may be
administered into the anterior segment of the eye, in particular
into the anterior chamber or posterior chamber of the eye, or into
the posterior segment of the eye.
[0024] Examples of procedures requiring pupil dilation and
associated with postoperative inflammation suitable for practice of
the present invention include cataract extraction and lens
replacement (CELR), refractive lens exchange (RLE), vitrectomy,
retinal photocoagulation, retinal detachment repair, macular hole
repair, retroiris tumor or mass removal, posterior sclerotomy and
optic neurotomy. CELR and RLE may involve femtosecond or scalpel
incision, phacoemulsification for lens removal and intraocular lens
(IOL) replacement. The present invention may also be used in
connection with the inhibition of inflammatory conditions resulting
from intravitreal injection, by injecting the solution of the
present invention together or concurrently with, or immediately
preceding or following, the injection of one or more other
therapeutic agents, such as an anti-vascular endothelial growth
factor (anti-VEGF) such as ranibizumab.
[0025] Ophthalmic surgeons typically use preoperative treatment
with mydriatic medications to dilate the pupil before surgery.
Behndig, A., et al., "Intracameral mydriatics in cataract surgery,"
Cataract Surgery, Zaidi F. (ed.), Rijeka, Croatia: InTech
2013:149-172. The larger and longer the pupil stays dilated with
one or more mydriatic agents, the easier and less risky the
procedure. Pupil constriction during surgery makes the procedure
more difficult and increases the risk of additional complications.
(Behndig 2013)
Postoperative Inflammation
[0026] Most cataract procedures are routine and uncomplicated.
Patalano, V. J., "The risks and benefits of cataract surgery,"
Digital Journal of Ophthalmology,
http://www.djo.harvard.edu/site.php?url=/patients/pi/408, Accessed
Jun. 26, 2014; A.D.A.M., Inc., "Cataracts In-depth report," The New
York Times,
http://www.nytimes.com/health/guides/disease/cataract/print.html,
accessed Jun. 26, 2014. But the occurrence of intraoperative
complications is often unpredictable and estimated to be associated
with 3.8% of cataract procedures in the United States. (Patalano
2014); Greenberg, P. B., et al., "Prevalence and predictors of
ocular complications associated with cataract surgery in United
States veterans," Ophthalmology 118(3):507-514 (2011).
[0027] Intraoperative miosis makes the cataract surgical procedure
more difficult by shrinking the surgeon's visual field and working
space. (Behndig 2013) A small pupil during surgery is associated
with increased risk of intraoperative complications, including
posterior capsule rupture and vitreous loss. Artzen, D., et al.,
"Capsule complication during cataract surgery: Case-control study
of preoperative and intraoperative risk factors: Swedish Capsule
Rupture Study Group report 2," J Cataract Refract Surg
35(10):1688-1693 (2009); Zare, M., et al., "Risk factors for
posterior capsule rupture and vitreous loss during
phacoemulsification," J Ophthalmic Vis Res. 4(4):208-212 (2009).
Reduced visibility and room for surgical maneuvering may also lead
to an increased chance of losing a portion of the lens or the whole
lens nucleus into the vitreous cavity (dropping the nucleus) or
causing injury to the iris. (Behndig 2013)
[0028] Intraoperative miosis is frequently associated with
intraoperative floppy iris syndrome (IFIS). Eyes with IFIS have
loose, billowy iris tissue with increased risk of prolapse and
pupil constriction during surgery. Chang, D. F., Campbell, J. R.,
"Intraoperative floppy iris syndrome associated with tamsulosin," J
Cataract Refract Surg 31(4):664-673.22 (2005); Chang, D. F., et
al., "Prospective multicenter evaluation of cataract surgery in
patients taking tamsulosin (Flomax)" Ophthalmology 114(5):957-964
(2007). The number of IFIS cases is known to be especially high
among patients who have received treatment with an
.alpha.1-adrenergic receptor antagonist, such as tamsulosin
(Flomax). (Chang 2005); Haridas, A, et al., "Intraoperative floppy
iris syndrome (IFIS) in patients receiving tamsulosin or
doxazosin-a UK-based comparison of incidence and complication
rates" Graefes Arch Clin Exp Ophthalmol 251(6):1541-1545 (2013).
Tamsulosin is used for the treatment of patients with benign
prostatic hyperplasia (noncancerous enlargement of the prostate).
Significant intraoperative miosis has been shown to occur in more
than 70% of these high-risk patients, even when surgery was
performed by highly experienced cataract surgeons. (Chang
2007).
[0029] Surgical trauma causes intraocular inflammation, even if the
procedure is routine and uncomplicated. Lobo, C., "Pseudophakic
cystoid macular edema," Ophthalmologica 227(2):61-67 (2012);
Miyake, K., Ibaraki, N., "Prostaglandins and cystoid macular edema"
Surv Ophthalmol 2(47 suppl 1):S203-S18 (2002). Inflammation usually
begins in the anterior chamber, either at the site of surgical
entry or due to direct mechanical stimulation of intraocular
structures such as the iris or ciliary body. Early inflammatory
pathways are self-perpetuating, which means that inflammation
initially grows in intensity and spreads from the anterior chamber
to the vitreous and retina. (Lobo 2012); (Miyake 2002).
[0030] Inflammation is associated with vessel dilation and vascular
leakage. When the eye is inflamed after surgery, retinal vessels
leak and the accumulation of excess fluid causes retinal swelling,
or edema. (Lobo 2012); (Miyake 2002). Swelling can include the
macula, a specialized zone of the central retina that provides
sharp detailed vision used in tasks like reading or driving.
Retinal swelling that involves the macula is called macular edema.
Cystoid macular edema (CME) is defined by the presence of
anatomically distinct fluid pockets, or cysts. Ismail, R., Sallam,
A., "Complications associated with cataract surgery," Cataract
Surgery, Zaidi F. (ed.), Rijeka, Croatia: InTech 2013:221-244.
Inflammation and increased levels of intraocular prostaglandins
after cataract surgery have been identified as a cause of CME, and
there is an association between severe anterior ocular inflammation
and postsurgical CME. Rossetti, L., Autelitano, A., "Cystoid
macular edema following cataract surgery," Opin Ophthalmol 11:65-72
(2000).
[0031] Cystoid macular edema (CME) is a primary cause of reduced
vision following both cataract and successful vitreoretinal
surgery. Loewenstein, A., Zur, D., "Postsurgical Cystoid Macular
Edema," Macular Edema, Dev Ophthalmol., Coscas, G. (ed.), Basel,
Karger 2010:148-159. CME also remains a problem following
capsulotomy, penetrating keratoplasty, scleral buckling, filtering
procedures, and panretinal photocoagulation. (Loewenstein 2010);
Shimura, M., et al., "Panretinal photocoagulation induces
pro-inflammatory cytokines and macular thickening in high-risk
proliferative diabetic retinopathy," Graefes Arch Clin Exp
Ophthalmol 11:65-72 (2000). Estimates of postoperative CME
incidence depend on the definition and the method of detection.
Studies estimate the prevalence of CME after cataract surgery to be
between 4% and 20%. Wielders, L., et al., "Prevention of CME after
cataract surgery," Cataract Refract Surg Today Eur. 53-55 (2013).
CME does not lead to decreased vision in every case, or decreased
vision may be minor and imperceptible to the patient. Clinically
significant macular edema is associated with visual impairment and
estimated to occur in up to 5.8% of eyes after cataract surgery.
(Lobo 2012); (Wielders 2013).
[0032] An in vivo study evaluated prostaglandin accumulation in the
aqueous humor following paracentesis in rabbits as a model of
ocular surgical trauma. The concentration of PGE.sub.2 in the
aqueous humor peaked at one hour following paracentesis and
remained substantially elevated for seven hours post paracentesis,
approaching baseline levels 48 hours after surgical insult. Graff,
G. et al., "Transient loss of prostaglandin synthetic capacity in
rabbit iris-ciliary body following anterior chamber paracentesis,"
Ocular Immunology and Inflammation 6(4):227-238 (1998). This study
illustrates that once the inflammatory cascade is initiated during
ocular surgical trauma, prostaglandin levels remain elevated for a
prolonged period, potentially leading to undesired postoperative
conditions associated with excess inflammation.
Postoperative Inflammatory Conditions
[0033] Excess inflammation induced by ophthalmologic surgery can
result in a number of undesired postoperative conditions, and the
methods and composition of the present invention may be used to
inhibit or reduce the severity or incidence of these conditions.
Toxic anterior segment syndrome (TASS) is an acute postoperative
inflammatory reaction in which a noninfectious substance enters the
anterior segment and induces toxic damage to the intraocular
tissues. Almost all cases occur after uneventful cataract surgery,
and, more recently, it has been reported after phakic intraocular
lens implantation. This syndrome was previously defined by other
names, such as sterile endophthalmitis or postoperative uveitis of
unknown cause. Furthermore, a condition termed toxic endothelial
cell destruction (TECD) syndrome has been described and is believed
to be a variant of TASS. Nonsteroidal anti-inflammatory drops have
been shown to be a helpful adjunct in several cases of TASS,
supporting that TASS is mediated by inflammation. Al-Ghouri, A. R.,
M.D., "Toxic Anterior Segment Syndrome,"
http://emedicine.medscape.com/article/1190343-overview, accessed
Nov. 23, 2014.
[0034] Cystoid macular edema (CME) is a painless condition in which
swelling or thickening occurs of the central retina (macula) and is
usually associated with blurred or distorted central vision. Less
common symptoms include metamorphopsia, micropsia, scotomata, and
photophobia. CME is a relatively common condition and is frequently
associated with various ocular conditions, such as age-related
macular degeneration (AMD), uveitis, epiretinal membrane,
vitreomacular traction, diabetes, retinal vein occlusion,
medicine-related, or following ocular surgery. When CME develops
following cataract surgery and its cause is thought to be directly
related to the surgery, it is referred to as Irvine-Gass syndrome
or pseudophakic CME. Medical therapy of Irvine-Gass syndrome
includes NSAIDs, corticosteroids, and carbonic anhydrase
inhibitors. Recent advances in cataract surgery, such as
phacoemulsification, small-incision surgery and advances in
foldable intraocular lenses, have resulted in the decrease of
physical trauma associated with cataract surgery. The decrease in
the physical surgical trauma decreases the release of
prostaglandins, which are the main players in postoperative ocular
inflammation. However, postoperative inflammation continues to be a
cause of patient discomfort, delayed recovery and, in some cases,
suboptimal visual results. Left untreated, this inflammation might
interfere with patients' rehabilitation and/or contribute to the
development of other complications, such as cystoid macular edema.
Topically applied NSAIDs are commonly used in the management and
prevention of non-infectious ocular inflammation and cystoid
macular edema following cataract surgery. Colin, J., "The Role of
NSAIDs in the Management of Postoperative Ophthalmic Inflammation,"
Drugs 67(9):1291-308 (2007).
[0035] Although the most common cause of cystoid macular edema
(CME) is due to Irvine-Gass syndrome of CME after cataract
extraction or other intraocular surgery, i.e., pseudophakic cystoid
macular edema, numerous other conditions are associated with the
clinical appearance of fluid-filled cystoid spaces in the macular
region, i.e., nonpseudophakic cystoid macular edema. CME is a final
common pathway of many intraocular diseases, usually involving the
retinal vasculature. The appearance can differ somewhat, depending
on the etiology; however, CME can appear as a nonspecific clinical
finding. If the cause of CME is not obvious, detailed
ophthalmoscopy and, occasionally, ancillary testing may be
necessary to identify the cause. The most common drugs used to
treat CME include steroids, nonsteroidal anti-inflammatory drugs
(NSAIDs), and acetazolamide. Roth, D. B., M.D., "Nonpseudophakic
Cystoid Macular Edema,"
http://emedicine.medscape.com/article/1225735-overview#showall,
accessed Nov. 23, 2014.
[0036] Inflammation also appears to play a role in acute
postoperative endophthalmitis, and the inventors believe that the
present invention may be suitable for ameliorating this condition.
The use of intravitreal dexamethasone in the treatment of acute
postoperative endophthalmitis remains controversial. Clinicians
have used this short-acting corticosteroid to inhibit the
inflammatory effects of bacterial endotoxins, host factors, and
antibiotics. In a rabbit model of virulent infectious
endophthalmitis, dexamethasone was shown to decrease elimination of
intraocular vancomycin through the trabecular meshwork, suggesting
a new potential benefit to steroid administration. Clark, W. L.,
M.D., "Postoperative Endophthalmitis Treatment & Management,"
http://emedicine.medscape.com/article/1201260-treatment, accessed
Nov. 23, 2014. Nonsteroidal anti-inflammatory drugs may offer
equivalent anti-inflammatory efficacy (for both postoperative
inflammation and cystoid macular edema) without the typically
corticosteroid-associated adverse events. Rowen, S., "Preoperative
and Postoperative Medications Used for Cataract Surgery," Curr Opin
Ophthalmol. 10(1):29-35 (1999).
[0037] The present invention may also suitably be used to inhibit
postoperative posterior capsule opacification or anterior capsule
contraction. In about 20 percent of patients, the posterior portion
of the capsule becomes hazy some time during cataract surgery
recovery or even months later, causing posterior capsule
opacification. Posterior capsule opacification occurs because lens
epithelial cells, remaining after cataract surgery, have grown on
the capsule. Knobbe, C. A., M.D., "Cataract Surgery Complications,"
http
://www.allaboutvision.com/conditions/cataract-complications.htm,
accessed Nov. 23, 2014. Sustained-release celecoxib (an NSAID) from
incubated acrylic intraocular lenses has been shown to suppress
lens epithelial cell growth in an ex vivo model of posterior
capsule opacity. Davis, J. L., et al., "Sustained-release Celecoxib
From Incubated Acrylic Intraocular Lenses Suppresses Lens
Epithelial Cell Growth in an Ex Vivo Model of Posterior Capsule
Opacity," J Ocul Pharmacol Ther. 28(4):359-68 (2012).
[0038] The present invention may also be suitably used to inhibit
herpes simplex virus keratitis after cataract surgery. Ocular
infection with herpes simplex virus (HSV) results in a blinding
immunoinflammatory stromal keratitis (SK) lesion. Early preclinical
events include polymorphonuclear neutrophil (PMN) infiltration and
neovascularization in the corneal stroma. HSV infection of the
cornea has been demonstrated to result in the upregulation of the
cyclooxygenase 2 (COX-2) enzyme. The induction of COX-2 by HSV
infection is a critical event, since inhibition of COX-2 with a
selective inhibitor has been shown to reduce corneal angiogenesis
and SK severity. The administration of a COX-2 inhibitor has been
shown to result in reduced PMN infiltration into the cornea as well
as diminished corneal vascular endothelial growth factor levels,
likely accounting for the reduced angiogenic response. Biswas, P.
S., et al, "Role of Inflammatory Cytokine-induced Cyclooxygenase 2
in the Ocular Immunopathologic Disease Herpetic Stromal Keratitis,"
J Virol 79(16):10589-600 (2005).
[0039] The nonsteroidal anti-inflammatory drug ketorolac may
prevent post-surgical hypotony due to cyclooxygenase products that
are released during cataract surgery and other procedures,
indicating further utility for the present invention. A study
evaluating inhibition of PGE.sub.2 production by ketorolac,
bromfenac and nepafenac in patients undergoing phacoemulsification
demonstrated that ketorolac 0.45% achieved the greatest inhibition
of PGE.sub.2 compared to nepafenac 0.1% and bromfenac 0.09. Bucci,
F. A., Jr., et al., "Prostaglandin E2 Inhibition of Ketorolac
0.45%, Bromfenac 0.09%, and Nepafenac 0.1% in Patients Undergoing
Phacoemulsification," Adv Ther 28(12):1089-95 (2011). The
possibility of an acute increase in intraocular pressure (IOP)
following laser iridotomy is well known. A study has shown that
laser irradiation of the iris itself can also cause ocular
hypotony, so that this phenomenon may be another explanation of the
IOP response after peripheral iridoplasty. Kim, Y. Y., et al.,
"Biphasic Intraocular Pressure Response to Laser Irradiation of the
Iris in Rabbits," Ophthalmic Res 27(4):243-8 (1995).
[0040] Nylon suture toxicity may also result in postoperative
inflammation and be suitably inhibited by use of the present
invention. A cluster of symptoms and signs that developed in 10 of
105 consecutive patients (9.5%) who underwent uncomplicated planned
extracapsular cataract extraction (ECCE) with posterior chamber
intraocular lens (PC IOL) implants has been reported as appearing
to be related to wound closure. These signs and symptoms included
foreign body sensation, conjunctival injection and infiltrates
localized to the scleral wound, and scleral excavation underlying
the running 10-0 nylon suture possibly resulting from localized
scleral edema. The time of clinical presentation ranged from 1 to 6
weeks. Conjunctival stains demonstrated eosinophils and
polymorphonuclear leukocytes in some cases. Gram stains,
conjunctival cultures, and results of suture toxicology studies
were negative. Balyeat, H. D., et al., "Nylon Suture Toxicity After
Cataract Surgery," Ophthalmology 95(11):1509-14 (1988).
[0041] Cataract surgery can in some cases result in long-term
corneal endothelial cell loss, while vitrectomy may result in
corneal edema, both conditions that may be inhibited by the present
invention. Three-day and 1-day dosing of ketorolac has been shown
to reduce surgical time, phacoemulsification time and energy, and
endothelial cell loss and improved visual acuity in the immediate
postoperative period compared with 1-hour predosing or use of a
placebo. Donnenfeld, E. D., et al., "Preoperative Ketorolac
Tromethamine 0.4% in Phacoemulsification Outcomes:
Pharmacokinetic-response Curve," J Cataract_Refract Surg.
32(9):1474-82 (2006); Hiraoka, M., et al., "Factors Contributing to
Corneal Complications after Vitrectomy in Diabetic Patients," Jpn J
Ophthalmol. 45(5):492-5 (2001). Ketorolac tromethamine 0.5%
ophthalmic solution has been shown to be effective and
well-tolerated in controlling postoperative inflammation. Simone,
J. N., "Comparison of the Efficacy and Safety of Ketorolac
Tromethamine 0.5% and Prednisolone Acetate 1% after Cataract
Surgery," J Cataract Refract Surg. 25(5):699-704 (1999).
[0042] Intraocular lens implantation may be associated with a
corneo-retinal inflammatory syndrome that leads to corneal
decompensation and cystoid macular edema. The inflammatory aspects
often do not appear striking but manifest as mild ciliary flush,
mild flare, moderate cells in the anterior chamber, and moderate
vitritis. The cornea will decompensate in the presence of
endothelial cell counts which are sufficient to maintain corneal
clarity in the non-inflamed eye. Metal-looped lenses and poorly
polished lenses cause iris chafing and capillary leakage, which
increase the severity of this syndrome. It is postulated that
intraocular surgery initiates an inflammatory response that is
augmented by certain components of intraocular lenses. The
mediation for this increased inflammatory response may be inhibited
by both steroidal and non-steroidal anti-inflammatory agents. The
presence of white blood cells and their products, such as lysosomal
enzymes, may be sufficient to perpetuate the inflammatory response
and cause damage to abnormal and normal cells. The presence of
protein and its immune components, as well as complement, may be
involved in this syndrome. Obstbaum, S. A., et al., "Cystoid
Macular Oedema and Ocular Inflammation. The Corneo-Retinal
Inflammatory Syndrome," Trans Ophthalmol Soc U K. 99(1):187-91
(1979).
[0043] Postsurgical scleritis and episcleritis may also be
inhibited by use of the present invention. A number of cases of
necrotic sclerokeratitis following eye surgery have been reported
in recently published literature. The condition was presumably
triggered by surgical inflammation and caused by localized
occlusive vasculitis: in one case deposits of immune complexes in
vessel walls were demonstrated. Clinical examination shows
disappearance of vessels in affected sclera, together with tissue
necrosis. Gregersen, E., et al., "Necrotizing Sclerokeratitis
Following Cataract Extraction," Klin Monbl Augenheilkd.
193(6):642-4 (1988). In a report of 21 cases, out of a total of 682
cataract patients, of surgically induced diffuse scleritis (SIDS)
following planned extracapsular cataract extraction with
intraocular lens insertion, the mean age was found to be
significantly lower in the patients with SIDS (mean 62.5 years; SD
13.68) when compared with the non-scleritic group (mean 73.6 years;
SD 10.2; Mann-Whitney U-test, p=0.0003). There was an association
of SIDS with general anesthesia (chi-squared test, p=0.0008).
Twenty of the 21 patients with SIDS responded to oral non-steroidal
anti-inflammatory agents with good visual result. Scott, J. A., et
al., "Surgically Induced Diffuse Scleritis Following Cataract
Surgery," Eye (Lond). 8 (Pt 3):292-7 (1994).
[0044] Vitreous wick syndrome occurs after eye surgery and consists
of microscopic wound breakdown, followed by a vitreous prolapse
that develops into a vitreous wick, and may also be suitably
inhibited by practice of the present invention. Vitreous wick
syndrome develops in the setting of trauma, either iatrogenic or
noniatrogenic. Vitreous wick syndrome of iatrogenic origin usually
follows anterior-segment surgery, though it may also follow
subtenon injection and muscle surgery. Corneal wound healing has
been documented to be slower on the endothelial side (inner
layers). Poor suturing technique is implicated as a major factor
for wound breakdown. Tightly compressed corneal wound edges may
demonstrate puckering and also may lead to enlargement of suture
tracts, promoting tissue necrosis within the suture loop. Once
communication between the posterior wound gap and the anterior
wound defect occurs (subsequent to tissue necrosis from tight
sutures), anterior aqueous fluid may egress; vitreous incarceration
may also occur, producing the vitreous wick. Occasionally, complete
sloughing of strangulated tissue within the suture loop may occur.
Rogue, M. R., M.D., M.B.A., F.P.A.O, "Vitreous Wick Syndrome.,"
http://emedicine.medscape.com/article/1230457-overview#a0101,
accessed Nov. 23, 2014. A study comparing the force required to
separate corneal wounds after topical applications of nonsteroidal
anti-inflammatory drugs or corticosteroids found that steroid
treatment caused weaker corneal wound scars than did NSAIDs.
McCarey, B. E., et al., "Corneal Wound Healing Strength with
Topical Antiinflammatory Drugs," Cornea 14(3):290-4 (1995).
[0045] Post-operational acute iridocyclitis, or post-surgical
inflammation of the iris and ciliary body, also provides a
treatment opportunity for the present invention. Evaluation of the
adjunctive use of nonsteroidal anti-inflammatory drugs for the
treatment of chronic iridocyclitis in 14 patients has been
reported, eight of whom had juvenile rheumatoid arthritis and six
with idiopathic iridocyclitis. In all patients, the activity of the
iridocyclitis improved with the addition of NSAIDs to their
treatment regimens, permitting reduction in the dose of
corticosteroid drugs. These data suggest that NSAID therapy may
have an adjunctive role in the treatment of chronic iridocyclitis
in childhood. Olson, N. Y., et al., "Nonsteroidal anti-inflammatory
drug therapy in chronic childhood iridocyclitis," Am J Dis Child
142(12):1289-92 (1988). Cataract is an early complication of
juvenile idiopathic arthritis-associated uveitis. Under strict
control of uveitis, IOL implantation is an important alternative in
visual rehabilitation for this type of patient. Control of uveitis
with NSAIDs before, during and after cataract surgery presents a
further utility for the present invention. Kotaniemi, K., et al.,
"Intraocular Lens Implantation in Patients with Juvenile Idiopathic
Arthritis-Associated Uveitis," Ophthalmic Res. 38(6):318-23
(2006).
[0046] The present invention may additionally be used to inhibit
inflammation due to epiretinal deposits after cataract extraction.
In a report of two patients identified with epiretinal deposits
after cataract extraction where the posterior capsule barrier was
breached, inflammation was found to be limited to the posterior
segment, and investigative work-up for infective causes was
negative. Behera, U. C., "Epiretinal Deposits Post Cataract
Extraction," Retin Cases Brief Rep. 7(4):359-61 (2013).
[0047] Reiterative membranous proliferation with giant-cell
deposits may follow some cases of cataract surgery. One report
addresses the outcomes of a 72-year-old Japanese woman and a
67-year-old Japanese man who underwent AcrySof IOL (SA60AT)
implantation in their eyes (both eyes in the first case and the
left eye in the second case) for the treatment of cataract and
vitreous opacity with uveitis. Although intraocular inflammation
seemed to be successfully controlled, the number of giant-cell
deposits on the posterior surface of the posterior capsule was
gradually increased with the development of posterior capsular
opacification in 5 and 9 months, respectively, and neodymium-doped
yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy was required.
Iwase, T., "Reiterative Membranous Proliferation With Giant-Cell
Deposits on Hydrophobic Acrylic Intraocular Lenses After Triple
Procedures in Eyes with Cataracts and Uveitis," Cutan Ocul Toxicol.
29(4):306-11 (2010).
[0048] A report of 11 cases of intraocular inflammation after
intravitreal injection indicates another suitable use of the
present invention. Only one of these cases involved infectious
endophthalmitis with retinal abscess, with all others involving
toxic vitreitis. Seven eyes exhibited hypopyon and five
disseminated retinal hemorrhages. The toxic reaction occurred
within 48 hours after injection, whereas in the endophthalmitis
case, it occurred after 72 hours. The cause of this reaction was
believed by the reporting authors to be the particular syringe
brand used. After changing to another syringe brand, no further
cases of toxic vitreitis occurred during the next 6 months. Ness,
T., et al., "Toxic Vitreitis Outbreak After Intravitreal
Injection," Retina. 30 (2):332-8 (2010).
[0049] A synechia is an eye condition where the iris adheres to
either the cornea (i.e., anterior synechia) or lens (i.e.,
posterior synechia), and instances of this condition following
surgical procedures may be inhibited by the present invention.
Synechiae can be caused by ocular trauma, iritis or iridocyclitis
and may lead to certain types of glaucoma. Topical corticosteroids
have conventionally been used to subdue the inflammation. Wikipedia
contributors, "Synechia (eye)," Wikipedia, The Free Encyclopedia,
http://en.wikipedia.org/wiki/Synechia_(eye), accessed Nov. 23,
2014.
[0050] The present invention may also be used to inhibit
postoperative intraocular fibrin formation. The anti-inflammatory
effect of 0.1% diclofenac sodium on anterior inflammation after
cataract surgery has been reported. Fibrin precipitation after
surgery in patients without systemic or ocular disease was markedly
less when diclofenac sodium ophthalmic solution was used in
combination with topical corticosteroids. There was also a
reduction in fibrin precipitation in other patients, especially in
those with diabetes mellitus, primary angle-closure glaucoma, and
exfoliation syndrome. Matsuo, K., et al., "Clinical Efficacy of
Diclofenac Sodium on Postsurgical Inflammation After Intraocular
Lens Implantation," Refract Surg. 21(3):309-12 (1995).
[0051] Four cases of incisional complications following pars plana
vitrectomy illustrate a utility of the present invention for the
inhibition of incisional fibrosis. As reported, in each instance
excessive fibrosis occurred at the wound site. In one patient, the
disorder was mild and did not lead to clinical difficulties during
his lifetime; however, in the three severe cases the eyes were lost
secondary to intraocular organization (fibrotic changes) and
phthisis bulbi. Possible contributing factors include diabetes
mellitus, excessive trauma and necrosis at the wound site,
postoperative inflammation, and vitreous involvement in the wound.
Kreiger, A. E., "Incisional Complications in Pars Plana
Vitrectomy," Mod Probl Ophthalmol. 18:210-23 (1977).
[0052] The present invention may be useful for treating choroidal
neovascularization and other complications following surgical
treatment for macular holes. In a reported study of complications
of vitrectomy surgery for full-thickness macular holes, posterior
segment complications were noted in 39 eyes (41%). The incidence of
retinal pigment epithelium alteration and retinal detachment were
33% and 11%, respectively. One case of retinal detachment due to a
giant retinal tear resulted in a visual acuity of light perception.
Other complications included a reopening of the macular hole in two
eyes (2%), cystoid macular edema in one eye (1%), a choroidal
neovascular membrane in one eye (1%) and endophthalmitis in one eye
(1%). Banker, A. S., "Vision-Threatening Complications of Surgery
for Full-Thickness Macular Holes. Vitrectomy for Macular Hole Study
Group," Ophthalmology. 104(9):1442-52 (1997). A pilot study has
been reported that suggests that topical ketorolac may supplement
the activity of intravitreal ranibizumab in reducing a mean
six-month change in central macular thickness in choroidal
neovascularization. Russo, A., et al., "A Randomised Controlled
Trial of Ranibizumab With and Without Ketorolac Eyedrops for
Exudative Age-Related Macular Degeneration," Br J Ophthalmol.
97(10):1273-6 (2013).
[0053] Choroidal effusion, which is an abnormal accumulation of
fluid in the suprachoroidal space, is a common complication of
glaucoma surgery and may suitably be inhibited by the practice of
the present invention. Choroidal effusion may also arise from other
intraocular surgical procedures as well as a number of conditions,
including inflammatory and infectious diseases, trauma, neoplasms,
drug reactions, and venous congestion. Idiopathic causes fall under
the umbrella of uveal effusion syndrome, a rare condition usually
considered a diagnosis of exclusion. Reddy, A. C., M.D, "Diagnosis
and Management of Choroidal Effusions,"
http://www.aao.org/publications/eyenet/201211/pearls.cfm?RenderForPrint=1-
&, accessed Nov. 23, 2014.
[0054] Hypopyon is seen as yellowish exudate in the lower part of
the anterior chamber of the eye and is formed of inflammatory
cells. It is a leukocytic exudate and is a sign of inflammation of
the anterior uvea and iris, i.e., iritis, which is a form of
anterior uveitis. Hypopyon has been reported in a patient with
rheumatoid arthritis undergoing phacoemulsification. This
70-year-old woman was on a maintenance dose of systemic
methylprednisolone at the time of uneventful phacoemulsification in
the left eye. She developed a sterile hypopyon on the first
postoperative day, which was treated aggressively with topical and
systemic therapy, resulting in a gradual resolution of the
inflammatory response. The patient subsequently had
phacoemulsification in the right eye. The only significant
difference in the preoperative management this time was that the
patient received topical ofloxacin and ketorolac four days before
surgery. The postoperative inflammatory response was much more
controlled. The patient was continued on ketorolac and prednisolone
acetate, resulting in the usual postoperative inflammatory
response. Caronia, R. M., "Antiinflammatory Effect of Preoperative
Ketorolac in Phacoemulsification," J Cataract Refract Surg.
28(10):1880-1 (2002). This report suggests that the present
invention may have utility for inhibition of hypopyon following
ocular surgery.
Predisposing Conditions
[0055] The present invention also provides a method for inhibiting
a postoperative inflammatory condition following an ophthalmologic
surgical procedure by identifying a subject with a physiologic risk
of suffering from a postoperative inflammatory condition and
administering intraocularly to the subject during an ophthalmologic
surgical procedure a solution including a nonsteroidal
anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor
agonist mydriatic agent in an intraocular irrigation carrier,
wherein the NSAID and the mydriatic agent are included in the
solution in amounts sufficient for the inhibition of the
postoperative inflammatory condition.
[0056] Small pupil size during surgery is also associated with
increased risk of intraoperative complication. (Artzen 2009); (Zare
2009). Studies have identified risk factors to help surgeons
predict which patients may be at risk of a complication during
surgery. Advanced age, previous ocular surgery, and diabetes with
ophthalmic manifestations are among patient-related factors that
have been associated with increased risk of intraoperative
complication. (Greenberg 2011). Individuals with diabetes mellitus
(DM) are often predisposed to developing cataracts; over 25% of
cataract patients are estimated to also have concomitant DM.
National Diabetes Clearing House, diabetes.niddk.nih.gov, Accessed
on Sep. 30, 2012.; Ostri C., et al., "Phacoemulsification cataract
surgery in a large cohort of diabetes patients: visual acuity
outcomes and prognostic factors," J Cataract Refract Surg
37(11):2006-2012 (2011). Individuals with DM who undergo cataract
surgery have a greater propensity towards intraoperative miosis
than individuals without DM. This may lead to more postoperative
complications such as development of postoperative cystoid macular
edema, worsening diabetic macular edema, progression to
proliferative diabetic retinopathy, and the development of rubeosis
iridis. Oetting, T., "Complicated cataract cases. Cataract surgery
and diabetes," ASCRS EyeWorld,
http://www.eyeworld.org/article-cataract-surgery-and-diabetes,
Accessed Nov. 25, 2014.
[0057] Systemic diseases, intraoperative complications and
preexisting ocular conditions are risk factors that influence the
development of CME. (Loewenstein 2010). Systemic risk factors for
postsurgical CME include diabetes mellitus, which promotes the
development of CME even in the absence of diabetic retinopathy.
Schmier J., et al., "Evaluation of costs for cystoid macular edema
refractory to topical medications," Ophthalmology 104:2003-2008
(1997). Systemic hypertension apparently increases the incidence of
postsurgical CME. Flach, A., "The incidence, pathogenesis and
treatment of cystoid macular edema following cataract surgery,"
Trans Am Ophthalmol Soc 96:557-634 (1998). Systemic hypertension is
also a risk factor for retinal vein occlusion, which itself
increases CME. (Loewenstein 2010).
[0058] Certain surgical complications also raise the risk of CME.
Rupture of the posterior capsule, as well as secondary capsulotomy,
including YAG capsulotomy, are associated with a higher rate of
CME. Vitreous loss increases the prevalence of CME by 10-20%. Iris
incarceration is an additional risk factor for CME, as are certain
types of intraocular lenses, specifically iris-fixated IOLs and
anterior chamber IOLs. (Loewenstein 2010). A review of patients
with CME following pars plana vitrectomy for retained lens
fragments demonstrated that 8% of eyes with a sulcus-fixated
posterior chamber IOL implanted at cataract extraction and 46% of
eyes with aphakia or an anterior chamber IOL developed CME. Cohen,
S., et al., "Cystoid macular edema after pars plana vitrectomy for
retained lens fragments, " J Cataract Surg 32:1521-1526 (2006).
[0059] Certain preexisting conditions also increase the risk of
postsurgical CME. These conditions may compromise the integrity of
the blood-retinal barrier and boost inflammatory activity. These
include uveitis, in which CME is the most important cause for poor
visual outcomes following cataract surgery. (Loewenstein 2010). As
noted above, preoperative diabetic retinopathy considerably
increases the risk of onset and persistence of CME (Iliff, W.,
"Aphakic cystoid macular edema and the operating microscope: is
there a connection?" Trans Am Ophthalmol Soc 83:476-500(1985)),
while a history of retinal vein occlusion and epiretinal membrane
(ERM) also predict development of CME. Henderson, B., et al.,
"Clinical pseudophakic cystoid macular edema. Risk factors for
development and duration of treatment," J Cataract Refract Surg
33:1550-1558 (2007). The topical use of latanoprost in glaucoma
patients has been reported in association with pseudophakic CME.
Warwar, R., et al., "Cystoid macular edema and anterior uveitis
associated with latanoprost use. Experience and incidence in a
retrospective review of 94 patients," Ophthalmology 105:263-268
(1998).
[0060] In accordance with an aspect of the present invention, a
subject to be treated with the NSAID and an alpha-1 adrenergic
receptor agonist solution of the invention is identified as having
an elevated risk of a postoperative inflammatory condition because
of a preoperative physiologic condition or characteristic including
small pupil diameter (e.g., a dilated preoperative pupil diameter
of less than 6 mm), floppy iris syndrome, uveitis, retinal vein
occlusion, epiretinal membrane, advanced age (e.g., over 65,
elderly or geriatric), diabetes mellitus, diabetic macular edema,
diabetic retinopathy, macular degeneration, or systemic
hypertension; a preoperative treatment history including previous
ocular surgery or pharmacologic treatment with an al-adrenergic
receptor antagonist or latanoprost; surgical trauma including
posterior capsule rupture, secondary capsulotomy, iris
incarceration, retained lens material, or vitreous loss; and the
surgical placement of nylon sutures, iris-fixated intraocular lens
or an anterior chamber intraocular lens. As used herein, "elevated
risk" of a postoperative inflammatory condition refers to a subject
whose risk of experiencing a postoperative inflammatory condition
following an ophthalmologic procedure is greater than the mean
incidence rate of the same postoperative inflammatory condition in
healthy subjects who do not have any predisposing risk
characteristics that are undergoing the same procedure.
[0061] Subjects at elevated risk of postoperative inflammation may
be identified by the surgeon in advance of surgery as having an
elevated risk of postoperative inflammation based on the patient's
preoperative physiologic condition or characteristic or
preoperative treatment history, or the planned placement of sutures
or intraocular devices that are associated with an enhanced
incidence of postoperative inflammation. Once identified, the
surgeon may administer the solution of the present invention during
the operative procedure to preemptively decrease or reduce the
incidence or severity of postoperative inflammation. Alternately
the surgeon may prophylactically administer the solution of the
present invention during the operative procedure to address an
enhanced risk of postoperative inflammation that may be identified
during the procedure due to the nature of surgical trauma, e.g.,
posterior capsule rupture, secondary capsulotomy, iris
incarceration, retained lens material, or vitreous loss, or
unplanned use of sutures or devices that are associated with an
enhanced incidence of postoperative inflammation.
Pharmacologic Agents
[0062] A broad variety of ophthalmologic surgical procedures induce
intraocular inflammation. As evidenced by the above described
paracentesis study, once the inflammatory cascade is initiated,
prostaglandin levels remain elevated for up to seven hours. The
method of the present invention provides for the intraoperative
delivery of a combination of an NSAID and an alpha-1 adrenergic
receptor agonist mydriatic agent. In a preferred embodiment of the
invention, the NSAID is ketorolac and the alpha-1 adrenergic
receptor agonist mydriatic agent is phenylephrine.
[0063] The impact of NSAIDs in inhibiting the formation of
prostaglandin by cyclooxygenase (COX) enzymes has been shown in
several studies to have an important impact on prevention of CME.
Wolf, E. J., et al., "Incidence of visually significant
pseudophakic macular edema after uneventful phacoemulsification in
patients treated with nepafenac," J Cataract Refract Surg
33:1546-1549 (2007); Cervantes-Coste, G., et al., "Inhibition of
surgically induced miosis and prevention of postoperative macular
edema with nepafenac," Clin Ophthalmol 3:219-226(2009); Donnenfeld,
E. D., et al., "Preoperative ketorolac tromethamine 0.4% in
phacoemulsification outcomes: pharmacokinetic-response curve," J
Cataract Refract Surg. 32:1474-1482 (2006).
[0064] Suitable non-steroidal anti-inflammatory drugs (NSAIDs) for
use in the present invention include flurbiprofen, suprofen,
diclofenac, ketoprofen, ketorolac, indomethacin, nepafenac and
bromfenac. A preferred NSAID is ketorolac. As used herein,
"ketorolac" means ketorolac in a salt form, such as ketorolac
tromethamine
[(+/-)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid:
2-amino-2(hydroxymethyl)-1,3-propanediol (1:1)]. Ketorolac in one
formulation of the present invention is included as the ketorolac
tromethamine salt
[(+/-)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic
acid:2-amino-2(hydroxymethyl)-1,3-propanediol (1:1)]. Ketorolac is
a member of the pyrrolo-pyrrole group of nonsteroidal
anti-inflammatory drugs. Ketorolac HCL is a racemic mixture of the
R-(+) and S-(-) enantiomers that may exist in three crystal forms,
all of which are equally soluble in water. Ketorolac is a
nonsteroidal anti-inflammatory that inhibits both cyclooxygenase
enzymes (COX-1 and COX-2), and when used in accordance with the
present invention results in a decrease in tissue concentrations of
prostaglandins to reduce pain due to surgical trauma. Ketorolac, by
inhibiting prostaglandin synthesis secondary to ocular surgical
insult or direct mechanical stimulation of the iris, also prevents
surgically induced miosis when used in accordance with the present
invention.
[0065] Suitable alpha-1 adrenergic receptor agonists for use as
mydriatic agents in the present invention include, for example,
phenylephrine, epinephrine, oxymetazoline and naphazoline. A
preferred alpha-1 adrenergic receptor agonist is phenylephrine. As
used herein, "phenylephrine" means phenylephrine in a salt form,
such as phenylephrine HCL [(-)-m-Hydroxy-a-[(methyl
amino)methyl]benzyl alcohol hydrochloride]. Phenylephrine is an
alpha-1 adrenergic receptor agonist and, in the eye, acts as a
mydriatic agent by contracting the radial muscle of the iris.
[0066] In accordance with the present invention, the NSAID and
alpha-1 adrenergic receptor agonist solution is administered
intraocularly by irrigation and/or injection during the procedure
to maintain pupil diameter by promoting mydriasis and inhibiting
miosis, thereby reducing surgical trauma to the iris and
intraocular structures manipulated through the iris. Thus the local
intraocular presence of both a mydriatic agent (e.g.,
phenylephrine) and an anti-miotic agent (e.g., ketorolac) during
the surgical procedure provide complimentary mechanisms to
preemptively limit trauma-induced inflammation during the
procedure. The in vivo study using paracentesis in a rabbit model
of surgical trauma described above (Graff 1998) demonstrates that,
following ocular surgical trauma, prostaglandin levels remain
elevated for a period of up to seven hours. The in vivo study in
dogs to determine the concentrations of ketorolac in the retina and
other ocular tissues following the intracameral administration of a
phenylephrine and ketorolac solution, described in Example 2 below,
demonstrates that the intraoperative uptake of ketorolac by retina
and other ocular tissues is surprisingly at levels sufficient to
inhibit COX-1 and COX-2 levels by at least 90% in ocular tissues
for at least 8 hours following drug administration, and by at least
85% in ocular tissues for at least 10 hours following drug
administration. Thus the present invention inhibits inflammation
during the surgical procedure, both by reducing trauma through
complimentary mydriatic and anti-miotic effects and by preemptively
inhibiting prostaglandin release, and continues to inhibit
inflammation during the period when postsurgical cyclooxygenase
levels are most elevated.
Formulations
[0067] The NSAID and alpha-1 adrenergic receptor agonist are
contained in an aqueous solvent as a carrier to provide a drug
composition or solution. The aqueous carrier is suitably water for
injection (WFI), which is a sterile, solute-free preparation of
distilled water. Alternately, other aqueous carriers that are not
harmful to intraocular tissues and which would not adversely affect
the stability of the formulation may be used, such as deionized
water, or, after first evaluating for potential impact on
stability, saline or a balanced salt solution such as that
described below.
[0068] The solution of the NSAID and alpha-1 adrenergic receptor
agonist of the present invention is suitably adjusted to a pH from
5.8 to 6.8, and preferably to about 6.3. Sodium hydroxide and
hydrochloric acid may be added as required to adjust the
formulation to this pH. The desired pH is suitably maintained by
use of a buffering system. One such suitable system is a citrate
buffer, including citric acid monohydrate and sodium citrate
dehydrate, and another suitable system is a sodium phosphate
buffer, including dibasic sodium phosphate and monobasic sodium
phosphate. Either buffer system may be used at an appropriate
concentration in the range of 10 mM to 100 mM, and suitably may be
20 mM. As described below in Example 1, sodium citrate is a
preferred buffer for use in a preservative- and antioxidant-free
formulation. The citric acid in the citrate buffer, which has the
ability to chelate divalent cations and can thus also prevent
oxidation, provides an antioxidant effect as well as a buffering
effect. As used herein, the term "antioxidant free" precludes the
use of other antioxidants but does not preclude the use of a
buffering agent, such as citric acid, that is included as part of
the buffering system.
[0069] The NSAID and alpha-1 adrenergic receptor agonist solution
of the present invention, e.g., a phenylephrine and ketorolac
combination drug solution, is suitably diluted into an intraocular
irrigation solution by injection into a bag, bottle or other
container of an intraocular irrigation solution prior to
administration by intraocular irrigation or injection. Suitable
intraocular irrigation solutions include saline, lactated Ringer's,
balanced salt solution or any other irrigation solution that is
compatible with the aqueous formulation and not harmful to ocular
tissues. One suitable intraocular irrigation carrier includes one
or more, and preferably all, of the following adjuvants: sufficient
electrolytes to provide a physiological balanced salt solution; a
cellular energy source; a buffering agent; and a free-radical
scavenger. One suitable solution (referred to in the examples below
as a "balanced salt solution" or "BSS" includes: electrolytes of
from 50 to 500 millimolar sodium ions, from 0.1 to 50 millimolar
potassium ions, from 0.1 to 5 millimolar calcium ions, from 0.1 to
5 millimolar magnesium ions, from 50 to 500 millimolar chloride
ions, and from 0.1 to 10 millimolar phosphate; bicarbonate as a
buffer at a concentration of from 10 to 50 millimolar; a cellular
energy source selected from dextrose and glucose, at a
concentration of from 1 to 25 millimolar; and glutathione as a
free-radical scavenger (i.e., antioxidant) at a concentration of
from 0.05 to 5 millimolar.
[0070] One example of a suitable method of diluting and
administering the preferred phenylephrine and ketorolac composition
of the present invention utilizes the formulation of the present
invention described in Table 1 below. An aliquot of 4.5 mL of this
solution, including 4.0 mL as the intended quantity for single use
and 0.5 mL of overfill, is contained within a sterile closed
single-use vial and is intended for admixture with irrigation
solution for administration during intraocular surgery. From the
vial, 4 mL is withdrawn by syringe and mixed with 500 mL of BSS by
injection into a 500-mL bag or bottle of BSS to provide a final
concentration of 483 .mu.M phenylephrine and 89 .mu.M ketorolac in
the irrigation solution for local delivery to the eye.
[0071] In another aspect of the invention, a sterile liquid
pharmaceutical formulation for irrigation may be provided in which
the phenylephrine and ketorolac are already admixed within an
intraocular irrigation carrier, such that it has been diluted to
the concentration of each active pharmaceutical ingredient desired
for local delivery to intraocular tissues during surgery, and
contained within a sterile bag, bottle or other irrigation
container. For example, such a formulation for irrigation may
include phenylephrine at a concentration of from 30 to 720 .mu.M
and ketorolac at a concentration of from 10 to 270 .mu.M, or
preferably may include the phenylephrine at a concentration of from
90 to 720 .mu.M and the ketorolac at a concentration of from 44 to
134 .mu.M.
[0072] As described above, an exemplary stable, liquid
pharmaceutical formulation of the present invention includes
phenylephrine and ketorolac in a buffered aqueous carrier. Suitable
concentrations of phenylephrine in the combination drug
compositions of the present invention range from 10 mM to 500 mM,
and preferably from 45 mM to 112 mM. Suitable concentrations of
ketorolac in the combination drug compositions of the present
invention range from 2 mM to 75 mM, and preferably from 8.5 mM to
24 mM. A buffer system, such as a sodium citrate buffer system, is
suitably included at a concentration of from 10 to 100 mM, and
preferably at about 20 mM. An exemplary formulation for use in
accordance with the present invention is set forth in Table 1
below. Sodium hydroxide and/or hydrochloric acid may be added when
preparing the formulation if necessary to adjust the pH to about
6.3.
TABLE-US-00001 TABLE 1 Example Formulation Component (USP)
Preferred Suitable Representative Diluted Dosing added to water for
Concentration Concentrations Concentration (.mu.M) injection mg/mL
mM mg/mL mM Preferred Suitable Phenylephrine HCl 12.37 60.75
9.2-15.5 45-76 483 240-720 Ketorolac 4.24 11.25 3.2-5.3 8.5-14 89
44-134 tromethamine Citric acid 0.24* 0.12-1.20** monohydrate
Sodium citrate 5.48* 2.74-27.4** dihydrate *Corresponding to a 20
mM citrate buffer. **Corresponding to a 10 mM to 100 mM citrate
buffer.
[0073] The amounts of pharmaceutically active ingredients included
in the formulation can be expressed in molar ratios. The molar
ratio of phenylephrine to ketorolac may range from 1:1 to 13:1, and
more suitably may range from 3:1 to 10:1. An exemplary molar ratio
of phenylephrine and ketorolac as represented in Table 1 above is
5.4:1 of phenylephrine to ketorolac.
[0074] Following dilution of this exemplary formulation of the
present invention into an intraocular irrigation carrier for local
delivery, the dosing concentration of phenylephrine may be from 3
to 7,200 more suitably from 30 to 720 more preferably from 90 to
720 still more preferably from 240 to 720 and most preferably about
483 .mu.M. Following dilution of the formulation of the present
invention into an intraocular irrigation carrier for local
delivery, the dosing concentration of ketorolac may be from 3 to
900 .mu.M, more suitably from 10 to 270 .mu.M, more preferably from
44 to 134 .mu.M, still more preferably from 30 to 90 .mu.M, and
most preferably about 90 .mu.M.
[0075] It must be noted that as used herein and in the appended
claims, the singular forms "a", "and", and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "an excipient" includes a plurality of such
excipients and equivalents thereof known to those skilled in the
art, and so forth. The term "about" as used herein is understood to
mean that there can be variation in a stated condition or amount
that can be to 5%, 10%, 15% or up to and including 20% of the given
value.
[0076] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed. All citations are
incorporated herein by reference.
EXAMPLES
Example 1
Clinical Studies Evaluating Phenylephrine 1%/Ketorolac 0.3% in
Cataract Surgery and Intraocular Lens Replacement For Maintenance
of Mydriasis and Prevention of Postoperative Pain
[0077] This example describes two Phase 3 clinical studies
performed to evaluate the efficacy and safety of phenylephrine 1%
and ketorolac 0.3% injection formulated as described in Table 1
above when used for the maintenance of mydriasis during, and
prevention of postoperative pain following, cataract surgery and
intraocular lens (IOL) replacement.
Methods
[0078] Two pivotal, multi-center, randomized, parallel-group,
double-masked, placebo-controlled phase 3 studies (Study 1 and
Study 2) that were conducted to support the use of phenylephrine 1%
and ketorolac 0.3% injection (OMS302) for maintaining
intraoperative mydriasis, preventing intraoperative miosis, and
reducing early postoperative ocular pain associated with cataract
surgery and IOL replacement. A total of 20 sites in the United
States and Netherlands enrolled subjects in these studies.
[0079] Subjects were randomized to receive either OMS302 or
placebo. A single administration of study drug, OMS302 (483 .mu.M
phenylephrine and 89 .mu.M ketorolac formulated in 20 mM sodium
citrate buffer) or placebo (20 mM sodium citrate buffer), was added
to balanced salt solution (BSS, 500 mL) and administered
intracamerally as part of the standard irrigation solution during
the procedure. Postoperative evaluations were conducted for up to
14 days (Study 1) or 90 days (Study 2); integrated safety analyses
were limited to data collected up to 14 days post-surgery. All
subjects (OMS302-treated and placebo-treated) in the studies
received standard-of-care preoperative topical mydriatic and
anesthetic agents.
[0080] Two co-primary endpoints were pre-specified for the
integrated analyses: 1) intraoperative pupil diameter during
surgery and 2) ocular pain during the early postoperative period
following surgery. Each subject's surgical procedure was video
recorded and change in pupil diameter was measured at one-minute
intervals from time of incision (surgical baseline) until wound
closure (surgical end) by a single, masked central reader.
Postoperative ocular pain was measured using a subject-assessed
visual analog scale (VAS) at 2, 4, 6, 8, and 10-12 hours after
surgery and on Days 2, 7, and 14.
[0081] Key secondary endpoints included pupil diameter <6 mm at
end of cortical clean-up, pupil diameter <6 mm at any time
during surgery, intraoperative pupillary constriction of
.gtoreq.2.5 mm, moderate-to-severe ocular pain (VAS.gtoreq.40) at
any time point assessed within the first 12 postoperative hours,
and no ocular pain (VAS=0) at all time points assessed within the
first 12 postoperative hours. Post-hoc secondary analyses included
categorization of subjects' intraoperative pupil constriction and
analgesic use on day of surgery.
Statistical Analysis
[0082] Each study was conducted independently. The sample size
calculations for the two studies were identical: a total of 400
subjects (200 subjects per treatment arm) in each study provided
99% power to detect a difference of 0.6 mm (standard deviation
[SD]: 0.7 mm) in mean area-under-the-curve (AUC) pupil diameter
change from baseline and 96% power to detect a difference of 5.0 mm
(SD: 13.3 mm) in mean AUC of ocular pain VAS during the first 12
postoperative hours using a two-sided t-test with .alpha.=0.05.
[0083] The mean AUC pupil diameter change from baseline during
surgery was calculated as follows: 1) the trapezoidal rule was used
to calculate the AUC of the pupil diameter from surgical baseline
to wound closure, 2) the result was divided by time of the last
pupil diameter value to obtain the mean AUC, and 3) the baseline
pupil diameter was subtracted from the mean AUC. The AUC of ocular
pain VAS during the first 10-12 postoperative hours was also
calculated using the trapezoidal rule with the mean AUC defined as
the AUC divided by the number of hours from the first VAS score to
the last VAS score within this time frame. For both primary
endpoints, a generalized Cochran-Mantel-Haenzel (CMH) test
stratified by randomization strata was used to compare the two
treatment arms for the two studies combined (LaVange, et al.
2005).
[0084] Treatment comparisons for all secondary efficacy analyses
presented were performed using Chi-square test or Fisher's exact
test if the frequency in a category was less than five. All
statistical analyses were performed using SAS software (version
9.3, SAS Institute, Inc., Cary N.C.).
Results--Efficacy
[0085] OMS302 was superior to placebo in maintaining mydriasis
during cataract surgery or IOL replacement procedures. Among 759
subjects with usable video images for determination of pupil
diameter, the mean AUC change-from-baseline in pupil diameter was
0.08 mm for the OMS302 group (n=379) compared to -0.50 mm for the
placebo group (n=380) and the CMH-weighted mean difference
(OMS302--placebo) (standard error [SE]) was 0.58 mm (0.04) (95%
confidence interval [CI]: 0.51, 0.65; p<0.0001). Following
initiation of surgery, baseline pupil diameter was maintained with
OMS302 treatment while progressive miosis was observed with placebo
treatment (FIG. 1). Results of secondary efficacy analyses
evaluating incidence of subjects with pupil diameter <6 mm at
completion of cortical clean up and at any time during surgery also
favored OMS302 treatment (Table 2). The proportions of subjects
with pupil diameter <6 mm at the time of cortical clean-up
completion, pupil diameter <6 mm at any time during surgery, and
degree of intraoperative pupillary constriction of .gtoreq.2.5 mm
were all significantly lower among OMS302-treated subjects than
placebo-treated subjects (p<0.0001 for each endpoint).
Considerably fewer OMS302-treated subjects than placebo subjects
experienced intraoperative pupil constriction greater than 1 mm
(FIG. 2).
TABLE-US-00002 TABLE 2 Supportive Efficacy Endpoints Placebo OMS302
(N = 405) (N = 403) Pupil Diameter Endpoints (includes subjects
with readable video data) Subjects with <6mm at cortical
clean-up 87/380 (22.9%) 15/379 (4.0%) p-value.sup.a <0.0001
Subjects with <6mm at any time during surgery 161/380 (42.4%)
37/379 (9.8%) p-value.sup.a <0.0001 Subjects with degree of
pupillary constriction.sup.b 103/380 (27.1%) 8/379(2.1%) >2.5 mm
p-value.sup.a <0.0001 Ocular Pain Endpoints (includes subjects
with complete VAS scores) Subjects pain free (VASA = 0) at all time
points.sup.c 69/403 (17.1%) 104/403 (25.8%) p-value.sup.a 0.0027
Subjects with moderate to severe pain (VAS .gtoreq. 40) 57/403
(14.1%) 29/403 (7.2%) at any time point p-value.sup.a 0.0014
Analgesic use on day of surgery 140/403 (34.7%) 99/403 (24.6%)
p-value.sup.a 0.002 .sup.aChi-Square test .sup.bMaximum decrease in
pupil diameter from baseline during surgery .sup.cSubjects with
missing VAS during 12 hours postoperatively are considered as not
being pain-free
[0086] Treatment with OMS302 was associated with a significant
reduction in early postoperative ocular pain compared to placebo.
Ocular pain VAS scores during the first 12 hours postoperatively
were more than 50% lower for the OMS302 group (mean AUC=4.16 mm,
n=403) than for the placebo group (mean AUC=9.06 mm, n=403). The
CMH-weighted mean difference (OMS302--placebo) (SE) in AUC of
ocular pain scores was -4.89 mm (0.80) (95% CI: -6.46, -3.31;
p<0.001). Mean VAS scores were lower among subjects treated with
OMS302 at each postoperative time point (FIG. 3). The proportion of
subjects who were ocular pain free (VAS=0) at all postoperative
time points was significantly higher for OMS302 compared to placebo
(25.8% vs 17.1%, respectively, p=0.0027; Table 2) and the
proportion of subjects with moderate-to-severe ocular pain
(VAS.gtoreq.40) at any postoperative time point was significantly
lower for OMS302 compared to placebo (7.2% vs 14.1%, respectively,
p=0.0014). Notably, in addition to lower VAS pain scores in the
OMS302 group, use of analgesics on the day of surgery was also
significantly lower among subjects treated with OMS302 compared to
placebo (24.6% vs 35.1%, respectively, p=0.0010).
Results--Safety
[0087] Of the 808 subjects (403 OMS302, 405 placebo) included in
the pooled safety analyses, 513 (63.5%) experienced at least one
treatment-emergent adverse event (TEAE). The proportion of subjects
reporting TEAEs was slightly lower among subjects receiving OMS302
(242/403 [60.0%]) than placebo (271/405 [66.9%]). The majority of
TEAEs were mild or moderate in severity. Only one serious adverse
event was reported in the two studies. This event (death due to
electrocution deemed unrelated to study drug) was also the only
event that resulted in premature discontinuation from the
studies.
[0088] The most frequently-reported TEAE consisted of eye pain
(reported by 35.1% of subjects overall), eye inflammation (15.5%),
anterior chamber inflammation (8.7%), headache (7.9%), intraocular
pressure increased (4.1%), posterior capsule opacification (4.1%),
ocular discomfort (4.1%), photophobia (4.0%), corneal edema (2.8%),
vision blurred (2.7%), conjunctival hyperemia (2.6%), and foreign
body sensation in the eyes (2.2%). These events were reported by
similar proportions of subjects in each treatment group with the
exception of eye pain, headache, ocular discomfort, photophobia,
and vision blurred, which were experienced by slightly more (>1%
difference between treatment groups) placebo subjects (40.0%, 9.4%,
5.2%, 4.9%, 4.2%, respectively) than OMS302 subjects (30.3%, 6.5%,
3.0%, 3.0%, 1.2%, respectively). Increased intraocular pressure was
the only common TEAE occurring in a slightly greater proportion
(>1% difference) of OMS302-treated subjects (4.7% OMS302 vs 3.5%
placebo).
[0089] Severe TEAEs were experienced by a total of 18 subjects (13
[3.2%] placebo subjects and 5 [1.2%] OMS302 subjects). Except for
the event of accidental electrocution experienced by a subject
treated with OMS302, all severe TEAEs consisted of eye disorders,
including eye inflammation (n=11), anterior chamber inflammation
(n=2), and conjunctival edema, corneal edema, conjunctival
hyperemia, eye pain, and photophobia (n=1 each). Of note, all
severe TEAEs considered to be related to study treatment occurred
among subjects receiving placebo. These events included two
instances of anterior chamber inflammation, and events of, corneal
edema, eye pain, photophobia, eye inflammation, and conjunctival
hyperemia.
[0090] Increased intraocular pressure was observed for several
subjects in both treatment groups following surgery. By Day 2,
increases compared to baseline were less notable; however, the
abnormality persisted in some subjects through the end of the
study. No notable TEAEs were reported in these subjects and no
differences in the proportions of subjects with increased
intraocular pressure were observed between the two treatment groups
on each evaluation day. In addition, no differences between
treatment groups were observed for any other serial assessments of
safety (i.e., vital signs or ophthalmological exams).
Conclusions
[0091] OMS302 was superior to placebo for the maintenance of
mydriasis during, and reduction of ocular pain following, IOL
replacement. The mean area-under-the-curve (AUC) change from
baseline in pupil diameter was 0.08 mm for OMS302 compared to -0.50
mm for placebo (p<0.0001). Mean AUC of subject ocular pain
visual analog scale (VAS) scores within 12 hours postoperatively
were over 50% lower for OMS302 (mean AUC=4.16 mm) than placebo
(mean AUC=9.06 mm, p<0.001). Results of all secondary efficacy
analyses demonstrated a significant treatment effect associated
with OMS302. Treatment-emergent adverse events were as expected for
a population undergoing IOL replacement; no clinically significant
differences in safety measures were observed between treatment
groups.
[0092] The integrated results of these two pivotal phase 3 studies
demonstrate the superiority of OMS302 compared to placebo in
maintaining pupil diameter and preventing miosis during, and
preventing postoperative ocular pain following, cataract extraction
with lens replacement or refractive lens exchange procedures, even
though all subjects received standard preoperative topical
mydriatics and anesthetics. The efficacy analyses were robust; AUC
analyses of the co-primary endpoints for the integrated analysis,
performed to show the aggregate effect of OMS302 on pupil diameter
during surgery and early postoperative pain, and all secondary
efficacy analyses were supportive. Furthermore, OMS302 was not
associated with any new or additional toxicities compared to
placebo. Common adverse events and safety findings (e.g., increased
intraocular pressure) observed in clinical studies of OMS302
performed to date are consistent with events commonly reported
among patients undergoing these procedures, and no clinically
significant differences between treatment groups were ob
served.
Example 2
Ocular Tissue Distribution of Ketorolac Following Administration of
Phenylephrine 1%/Ketorolac 0.3% to Dogs During Intraocular Lens
Replacement
[0093] This example describes the results of an in vivo study in
dogs to determine the concentrations of ketorolac in the retina and
other ocular tissues following the intracameral administration of
phenylephrine 1% and ketorolac 0.3% injection formulated as
described in Table 1 (OMS302) during IOL replacement in dogs.
Methods
[0094] IOL replacement by phacoemulsification was performed on 20
female beagles. During the procedure, OMS302 was administered in
BSS solution via irrigation and intracameral injection immediately
post-procedure. The target dose level of ketorolac was 5.71 mg/eye,
and the target dose volume of OMS302 diluted in BSS solution was
250 mL per eye. Four animals per time point were sacrificed at 0,
2, 6, 8, and 10 hours post-procedure. Samples of blood and aqueous
humor were collected. Enucleated eyes were frozen and dissected for
collection of retina, retinal pigmented epithelium-choroid, cornea,
iris-ciliary body, vitreous humor, sclera, and lens capsule. Tissue
concentrations of ketorolac were quantitated using a liquid
chromatography/mass spectrometry (LCMS) method. Using published
IC50 values for cyclooxygenase (COX) inhibition by ketorolac
(Waterbury, et. al., Curr Med Res Opin 22(6):1133-40 (2006)),
estimates of percent inhibition were derived for each time
point.
Results
[0095] FIGS. 4-6 illustrate the mean concentrations of ketorolac at
specified time points after the intracameral doses of OMS302, with
FIG. 4 showing ketorolac concentrations in the cornea, lens
capsule, iris-ciliary body (ICB), aqueous humor, and anterior
sclera; FIG. 5 showing ketorolac concentrations in the bulbar and
palpebral conjunctiva; and FIG. 6 showing the ketorolac
concentrations in vitreous humor, retina, choroid-RPE (peripheral),
choroid-RPE (tapetum), and posterior sclera. FIG. 7 shows the mean
percent inhibition of COX-1 and COX-2 in retinal tissues at t=0
through t=10 hours, based on an IC50 of 20 nM and a Ki of 10 nM for
COX-1 and an IC50 of 120 nM and a Ki of 60 nM for COX-2. Ketorolac
concentrations in the retina were 1400.+-.1004 ng/g immediately
following the end of IOL replacement, and 164.+-.39 ng/g at eight
hours post-procedure, corresponding to estimated COX-1/COX-2
inhibition of 99.3%/96.0% at t=0, and 98.4%/91.1% at t=8 hours. The
retinal half-life was .about.3.8 hours. Surprisingly, tissue
concentrations in aqueous humor, vitreous humor, and RPE-choroid at
t=8 hours were consistent with >90% inhibition of COX-1 and
COX-2. Also surprisingly, at t=10 hours, retinal tissue
concentrations were 97.74% (with a standard deviation of 0.36%) for
COX-1 and 87.82 (with a standard deviation of 1.75%) for COX-2. The
mean plasma level of ketorolac was 4.73.+-.1.46 ng/mL at t=0,
declining to undetectable levels at t.gtoreq.2 hours.
Conclusions
[0096] In this study, the use of OMS302 during IOL replacement
surgery resulted in the uptake of ketorolac by retina and other
ocular tissues at levels sufficient to inhibit COX-1 and COX-2
levels in intraocular tissues by greater than 90% for at least 8
hours, and by greater than 85% for at least 10 hours, following
drug administration in the intracameral irrigation solution, which
duration of action was unexpected. Systemic exposure was low and
transient.
Example 3
Clinical Study Evaluating Intracameral Ketorolac Concentration
Following Topical Ketorolac Administration Prior to Cataract
Surgery
[0097] This example describes the results of a clinical study to
determine postoperative intracameral concentrations of ketorolac in
subjects receiving topical ketorolac prior to cataract surgery.
Methods
[0098] Patients undergoing cataract extraction and lens replacement
(CELR) were eligible. Written informed consent was obtained from 14
subjects, each of whom received topical ophthalmic ketorolac
according to the surgeon's usual practice, beginning one day
preoperatively. Immediately prior to the initial surgical incision,
the surgeon withdrew a 100-.mu.L sample of aqueous humor from the
operative eye with a 30-gauge tuberculin syringe. At the conclusion
of CELR prior to final re-inflation of the anterior chamber and
wound closure, the surgeon withdrew another 100-.mu.L sample from
the anterior chamber. The ketorolac concentrations of the
intracameral fluid samples were analyzed by an analytical
laboratory.
Results
[0099] Thirteen of 14 subjects used four doses of ketorolac the day
prior to surgery, and one subject used three doses the day prior to
surgery. All 14 subjects received topical ketorolac in the surgery
center on the day of surgery. Aqueous humor samples were
inadvertently not collected from two subjects. The preoperative
ketorolac concentrations for the 12 subjects on whom samples were
collected ranged from 4.9 to 369 ng/mL. The end-of-procedure
samples ranged from <1.0 (the lower limits of quantification, or
LLOQ) to 6.32 ng/mL, with eight of the 12 subjects having ketorolac
levels below the LLOQ.
Conclusions
[0100] At-home compliance with topical ketorolac was generally
good, with 92.9% of subjects using topical ketorolac as directed.
Following CELR, levels of ketorolac in the aqueous humor at the end
of the surgical procedure were low, likely due to irrigation
wash-out, as 66.7% of subjects had an undetectable concentration of
ketorolac.
[0101] The in vivo and clinical studies of Examples 2 and 3,
respectively, demonstrate that intracamerally delivering ketorolac
in a ketorolac/phenylephrine solution during cataract and IOL
replacement surgery should result in a pharmacologically active
level of ketorolac in the eye for a substantially longer
postoperative time than results from topically delivering ketorolac
preoperatively, thereby providing for sustained postoperative
inflammation inhibition.
[0102] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it will be readily apparent to one of ordinary
skill in the art in light of the teachings of this invention that
certain changes and modifications may be made thereto without
departing from the spirit or scope of the appended claims.
* * * * *
References